Often, potentially effective biologic agents that demonstrate efficacy in preliminary research and testing will fail to be clinically useful when tested in clinical trials. It has been the observation of the inventor that many therapeutic agents have failed to yield a significant clinical response, even when the maximum dosage is utilized because of inefficient or ineffective modes of administration.
Under some circumstances, a medicine may be effective, but only at dosage levels that may cause toxicity. Often these undesirable side effects occur in tissues that are in sites distant to the intended site of action. Lowering the dose to non-toxic levels renders the drug ineffective with the standard methods of oral or parenteral administration. Even in the absence of toxicity therapeutic agents that have been shown to have effects on specific receptors often fail to yield any therapeutic clinical response in studies on living animals.
There are many examples of medications and treatments with biological agents that theoretically work in vivo, but show no significant effect when applied in vitro.
The systemic application of therapeutic agents to produce therapeutic effects in localized tissues is inefficient and dramatically increases the potential toxicity while limiting the potential effectiveness of the therapeutic agent.
It is a basic principle of pharmacokinetics that in order for a drug or therapeutic agent to be effective, it must be present in an appropriate concentration for an appropriate duration of time. If it does not reach an adequate concentration it cannot be effective. Even if it does reach a therapeutic concentration, if the therapeutic concentration is of too short duration the effect may not be clinically detectable.
The inventor has discovered that the systemic application of therapeutic agent(s) frequently fails to achieve a clinically significant effect for the simple reason that the drug or therapeutic agent is not present in an adequate concentration for an adequate duration of time. Due to regional variations in blood flow, medications and therapeutic agents may not be distributed homogeneously through the volume of tissue being treated in an adequate concentration for an appropriate duration of time. For example, to reach dense avascular structures such as tendons, ligaments, areas that have reduced vascular supplies such as infacted and devascularized tissues or regions of scarring and cirrhosis, regional areas that are naturally avascular such as tumors that have out grown their blood supply, or regions that have been traumatized by chemical, mechanical or thermal injury requires a dramatic increase in the size and frequency of systemically administered therapeutic agents in order to achieve an adequate therapeutic effect in those regions.
These factors affecting the heterogeneously variable concentration of therapeutic agents by various routes and methods of administering these agents are especially amplified when trying to systemically deliver therapeutic agents with relatively toxic therapeutic agents(=low therapeutic) index to areas with relatively limited perfusion, penetration or limited solubility.
For example, while the brain, heart, liver and kidneys receive a disproportionately high rate of blood flow (at rest the brain is 2% body weight and receives 25% of resting cardiac output, the kidney is 0.5% body weight and receives 20% of resting cardiac output, and the liver is 3% body weight and receives 15% of resting cardiac output and these vital organs will be subjected to increased toxicity. As well the gut and subsequently the liver also have a very disproportionate high level of blood supply immediately following any meal. As a result these essential organs are often the site of serious life threatening toxicity. Other therapeutic agent may exhibit very specific idiosyncratic reactions to these or other tissues such as the bone marrow. A therapeutic delivery device that could dramatically increase the effectiveness of a therapeutic agent(s) while reducing the total dose administered to achieve therapeutic levels by magnitudes of order would simultaneously increase effectiveness while dramatically reducing toxicity.
Even when medications are applied locally they can often fail to reach the intended site of action. In clinical situations where medications are self administered topically or by injection they will rarely be administered in frequencies of more than two to three times a day. And when medications are being administered parenterally in outpatient situations by health professionals, the dosing intervals may be even less frequent.
When patients or health professionals inject medications locally, the rate of injection is so rapid (when compared to the invention) it will not allow the medication to flow through the intercellular spaces but instead will result dissection through tissue plane resulting in isolated pockets of medication. When the therapeutic agent delivery device is used the rate of infusion can be titrated to the tissue site to ensure that the minimal flow rate can be used to yield this type of intercellular dispersion that avoids tissue dissection. This inventor asserts that this type of dispersion is magnitude of order faster than diffusion and requires magnitudes of order less medication being injected per unit of time in a much more uniform pattern of distribution. This contrasts with conventional local injections where the high rate of injection of relatively large volumes over short periods of time will dissect the tissue and leave localized pockets of medication with a much more uneven distribution.
And when the therapeutic agent delivery device is compared to systemic injections there is a even more dramatic reduction in the amount of therapeutic agent that will need to be administered by the therapeutic agent delivery device to achieve an equivalent therapeutic effect. This device can deliver medication to a plurality of topical sites for some clinical applications, or may require a plurality of parenteral delivery sites for other clinical applications.
This invention, as proposed for parenterally applied medication, will provide a controlled rate of volume per unit of time to a plurality of being delivered by slow continuous or frequent small intermittent infusions through a plurality of injection sites to produce a sustained and relatively continuous pressure gradient to allow continuous flow of the therapeutic agent through the intercellular and intermolecular tissue spaces which will effectively produce a more homogeneous dispersion of the therapeutic agent through a much larger volume of tissue. This much larger volume of distribution will dramatically improve the local diffusion and vascular redistribution to achieve much more uniform therapeutic levels between the plurality of therapeutic sites utilized by this invention.
Current state of art is to apply medications as individual doses through all possible routes of administration such as parenteral/injectable, inhalation, intranasal, sublingual, oral, rectal, or topical. Pharmakinetic studies are done by those skilled in the art to establish the highest safe dose, and then various lower doses are tested to establish the lowest optimal effective dose generally with the lowest risk of side-effects and/or toxicity.
Even through infusion pumps may be used, e.g. diabetes, or to inject intravenous medications at precisely controlled rate, e.g. morphine, for pain relief by IV drip, Syntocinon drip for induction of labor, these are medications applied at a distant site to deliver a Rx agent for a localized tissue effect that is distant for the site of intravenous infusion.
These various methods of delivering biological active agents fail if the agent cannot achieve and/or sustain an appropriately effective concentration at its intended site of action or if it induces unacceptable side effects.
Even though a medication may produce significant serum (venous) levels, actual tissue levels are in most clinical applications never tested. Even though tissue levels are assumed to closely approximate serum levels, in fact, many factors, from variations in regional blood flow and regional diffusion rate, distance the agent must diffuse to reach the site of action. These (multitude of factors; alone or in combination) may completely and/or functionally prevent the biological and/or pharmacological agent from acting effectively at the site of action.
There, thus, remains a need for a more efficacious method of delivering therapeutic agents to the desired site of action under many differing clinical situations.